The preservation of cognitive function throughout the lifespan is an important goal of aging research and is becoming more critical as our aging population grows. The aged canine model allows us to test hypotheses under controlled experimental conditions and to minimize the time interval between cognitive testing and neurobiological studies. In the previous grant period, we conducted a clinical trial to evaluate an antioxidant diet in combination with behavioral enrichment on measures of cognitive function and brain pathology. The antioxidant diet resulted in dramatic improvements in cognitive function in aged dogs and reduced the rate of decline. The antioxidant treated group showed a reduction in Abeta neuropathology, improved mitochondrial function and reduced oxidative damage. The first goal of the current proposal is to test specific hypothesis on the structural basis and molecular mechanisms underlying cognitive improving effects of treatment. The second goal is to test the hypothesis that the mitochondrial co-factors in the diet played a key role in reducing cognitive decline and neuropathology. To accomplish these goals, there are 3 specific aims: (1) Identify the neuronal mechanisms underlying the cognitive improving effects of behavioral enrichment and an antioxidant diet in tissues banked from our previous study. Studies will include identifying the mechanisms underlying Abeta reduction and improved mitochondrial function. Experiments will also be carried out to test the hypothesis that the treatment(s) alter molecules at the synapse and regulate neurogenesis. (2) Using a full factorial design, determine whether dietary treatment with mitochondrial co-factors alone (Group 1) results in cognitive improvements to a greater extent than cellular antioxidants alone (Group 2) or the control diet (Group 3) but similar to the complete antioxidant and mitochondrial co-factor diet used previously (Group 4);(3) Determine if treatment with mitochondrial co-factors will result in reduced brain pathology, improved mitochondrial function and reduced oxidative damage to an equal or greater extent than the 3 other treatment conditions. The outcome of the proposed studies provides critical insights into the role of mitochondria in the aging process, to determine neurobiological mechanisms underlying cognitive improving effects of individual treatment conditions and thus whether the appropriate interventions can promote successful cognitive and brain aging.